Cytotoxicity of Anthrax Lethal Toxin to Human Acute Myeloid Leukemia Cells Is Nonapoptotic and Dependent on Extracellular Signal-Regulated Kinase 1/2 Activity

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dc.contributor.author Abi-Habib, Ralph J.
dc.contributor.author Kassab, Elias
dc.contributor.author Timsah, Zahra
dc.contributor.author Liu, Shihui
dc.contributor.author Leppla, Stephen H.
dc.contributor.author Frankel, Arthur
dc.contributor.author Darwish, Manal
dc.date.accessioned 2015-12-01T08:26:14Z
dc.date.available 2015-12-01T08:26:14Z
dc.date.copyright 2013
dc.date.issued 2015-12-01
dc.identifier.issn 1944-7124 en_US
dc.identifier.uri http://hdl.handle.net/10725/2742
dc.description.abstract In this study, we attempt to target the mitogen-activated protein kinase (MAPK) pathway in acute myeloid leukemia (AML) cells using a recombinant anthrax lethal toxin (LeTx). LeTx consists of protective antigen (PrAg) and lethal factor (LF). PrAg binds cells, is cleaved by furin, oligomerizes, binds three to four molecules of LF, and undergoes endocytosis, releasing LF into the cytosol. LF cleaves MAPK kinases, inhibiting the MAPK pathway. We tested potency of LeTx on a panel of 11 human AML cell lines. Seven cell lines showed cytotoxic responses to LeTx. Cytotoxicity of LeTx was mimicked by the specific mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 (MEK1/2) inhibitor U0126, indicating that LeTx-induced cell death is mediated through the MEK1/2-extracellular signal-regulated kinase (ERK1/2) branch of the MAPK pathway. The four LeTx-resistant cell lines were sensitive to the phosphatidylinositol 3-kinase inhibitor LY294002. Co-treatment of AML cells with both LeTx and LY294002 did not lead to increased sensitivity, showing a lack of additive/synergistic effects when both pathways are inhibited. Flow cytometry analysis of MAPK pathway activation revealed the presence of phospho-ERK1/2 only in LeTx-sensitive cells. Staining for Annexin V/propidium iodide and active caspases showed an increase in double-positive cells and the absence of caspase activation following treatment, indicating that LeTx-induced cell death is caspase-independent and nonapoptotic. We have shown that a majority of AML cell lines are sensitive to the LF-mediated inhibition of the MAPK pathway. Furthermore, we have demonstrated that LeTx-induced cytotoxicity in AML cells is nonapoptotic and dependent on phospho-ERK1/2 levels. en_US
dc.language.iso en en_US
dc.title Cytotoxicity of Anthrax Lethal Toxin to Human Acute Myeloid Leukemia Cells Is Nonapoptotic and Dependent on Extracellular Signal-Regulated Kinase 1/2 Activity en_US
dc.type Article en_US
dc.description.version Published en_US
dc.author.school SAS en_US
dc.author.idnumber 200600671 en_US
dc.author.woa N/A en_US
dc.author.department Natural Sciences en_US
dc.description.embargo N/A en_US
dc.relation.journal Translational Oncology en_US
dc.journal.volume 6 en_US
dc.journal.issue 1 en_US
dc.article.pages 25-32 en_US
dc.identifier.doi http://dx.doi.org/10.1593/tlo.12313 en_US
dc.identifier.ctation Kassab, E., Darwish, M., Timsah, Z., Liu, S., Leppla, S. H., Frankel, A. E., & Abi-Habib, R. J. (2013). Cytotoxicity of anthrax lethal toxin to human acute myeloid leukemia cells is nonapoptotic and dependent on extracellular signal-regulated kinase 1/2 activity. Translational oncology, 6(1), 25-32. en_US
dc.author.email ralph.abihabib@lau.edu.lb
dc.identifier.url http://www.sciencedirect.com/science/article/pii/S1936523313800393

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